How the power of mRNA can be harnessed for cancer

Paradigm changing. Breakthrough. Revolutionary. These words are often associated with mRNA vaccine technology. And it’s for good reason—a lot of good reasons which could affect various medical specialities. Development of the technology began over 40 years ago as an obscure concept in cell biology. The idea was to find a way to harness the ability of mRNA to help certain cells inside a patient produce proteins for therapeutic purpose—a sort of on-demand drug factory for individuals. After numerous challenges, it evolved to a useable technology that led to the winning of a Nobel Prize by key pioneers in the field, Katalin Kariko, Ph.D. and Dr. Drew Weissman. Now, globally, researchers are advancing the technology to help treat everything from cancer, heart disease, HIV, rare diseases, chronic diseases and more. Much of the initial work on mRNA technology was to create a therapeutic vaccine for cancer, according to Pamela Ohashi, Ph.D., a professor of immunology at the University of Toronto. But then the pandemic happened, and companies that were working on cancer pivoted to developing COVID vaccines. The switch wasn’t too difficult because vaccinating against a virus is more straightforward than the complexities of cancer, she told the Medical Post. Now, while work continues in the realm of preventive vaccines against viruses, work in oncology has ramped up again. So, how can a vaccine that fights viruses fight cancer cells? How it works Once injected, mRNA, packaged in lipid which protects the mRNA from premature degradation, is absorbed by dendritic cells in the body where it instructs them to produce specific proteins that serve as a GPS for responding T cells, according to Dr. Richard Edelson, a professor of medicine at Yale University. His lab is one of three in the U.S. sharing a $25-million award, part of President Biden’s Cancer Moonshot program “Curing the Uncurable via RNA Encoded Immunogene Tuning.” With the COVID vaccine, the proteins that are produced are spike proteins, identical to the ones that sit on the surface of the virus. These unattached spike proteins teach the immune system to create antibodies that will disable anything with a spike protein, like the spike-adorned SARS-CoV-2 virus. At the same time, another part of the immune system, T cells, learn to recognize and destroy infected cells. The vaccine doesn’t stop people from becoming infected by the virus, it just makes the body really good at fighting it when it shows up. More importantly, because the players are in place in vaccinated people, the immune system is quick to respond. But with cancer, the idea is to teach the immune system to attack cancer cells, a more nuanced process. For one, “there is no way to create a vaccine that can prevent cancer, it has to be therapeutic,” said Dr. Edelson. Plus, every person’s cancer is unique. Cancer cells undergo numerous mutations, and the cancer cell’s set of mutations is different for each person’s cancer. This makes it impossible to create a one-fits-all treatment like you can with an antivirus vaccine—so current immunotherapy cancer treatments are more of a wide-spectrum approach, said Dr. Ohashi. Cancer cells can circumnavigate or suppress the immune system response. Immunotherapy uses various approaches to either give the immune system a boost to halt or slow cancer cell growth. But it’s not as specific as what mRNA promises, she said. “The mRNA vaccines offer a different strategy because it’s not pushing the already ongoing immune response. It’s starting a new immune response. This is a very important strategy because it will be applicable to many other patients and really improve immunotherapy,” she said. mRNA technology can be used to boost the immune system’s natural tendency to respond against cancer, specifically by boosting T cell activity, said Dr. Edelson. Thus far, mRNA vaccines are better at initiating antibody responses than T cell one. “The body naturally tries to make a T cell response against the vast majority of cancers that develop. So, normally, your body destroys incipient cancers way before we would ever see them,” he said. The idea is to use mRNA “to resurrect a reaction that’s been shut off.” In other words, increase the number of T cells that will attack cancer cells. This would be done by taking tumor samples from an individual patient, identifying the most promising neoantigens, creating a personalized mRNA therapeutic vaccine, and injecting it into the patient, he said. Dr. Ohashi noted that mRNA vaccines would also need to be human leukocyte antigen (HLA) matched to patients. The approach promises to lead to far fewer adverse reactions. “This is a very refined approach that will have very limited side effects. It’s quite simple in that many other treatments require some kind of hospitalization or anticipate side effects where you need to be in hospital. But this kind of lipid cancer vaccine—you would go in, get your shot, you would leave,” said Dr. Ohashi. Research is in its early days, but there are dozens of mRNA cancer vaccine clinical trials in progress around the world. Many are using mRNA vaccines in conjunction with immunotherapy. “If you want to count the number of cells that are elicited by a vaccine, it’s still very low. You end up getting 1% or 2% of T cells specific for the lipid particle mRNA vaccine. It’s not good enough yet to expand the number of T cells to huge numbers in patients. You need something to boost it,” she said. Dr. Edelson stated that this far, “results of the mRNA anticancer trials are encouraging but not yet ideal” which is why using other ways to boost immunity are needed. Over time “mRNA is going to get much better,” he said. The first successes will likely be in cancers that are more immunogenic, such as melanoma, non-small cell lung cancer and some kidney cancers. “Some of these cancers are particularly immunogenic. They’re easier to attack with the immune system,” Dr. Edelson said. But he feels that eventually many cancers will eventually be treated with mRNA therapeutic vaccines. An overview paper in Lancet Oncology listed numerous trials using mRNA vaccines for a variety of cancers, including glioblastoma, prostate cancer, head and neck squamous cell carcinoma, colorectal and ovarian cancers. Promising results of two trials were detailed at this year’s AACR conference. One was a small safety trial using customized vaccines in pancreatic ductal adenocarcinoma patients who also underwent surgical resection and other cancer treatments. At 18 months follow-up, a number of patients showed a correlation between vaccine response and delay in recurrence. Another was a phase-2 study of 157 patients with high-risk melanoma. The mRNA-4157/V940 vaccine was used in combination with the immune checkpoint inhibitor pembrolizumab and was found to improve recurrence-free survival in patients compared to pembrolizumab alone. “The mRNA story has begun to blossom but still has quite a way. It;s not prime time yet for cancer but the odds are that it is going to get there,” Dr. Edelson said.

How the power of mRNA can be harnessed for cancer

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